16-difluoromethyl adrenocorticoids



United States Patent 3,155,695 IrS-DIFLUDRQMETHYL ADRENOCORTICQEDS Albert Bowers and John Edwards, Mexico City, Mexico, assignors, by means assignments, to Syntex Corporation,

a corporation oi Panama No Drawing. Filed Get. 18, 1960, er. No. 63,267 Claims priority, application Mexico July 2, 1960 15 Claims. (Cl. 260-397.45)

The present invention relates to novel cyclopentanophenanthrene derivatives and to a novel process for the production thereof.

More particularly the present invention relates to novel l6ot-trifiuoromethyl, loa-difluorornethyl and l6a-monofluorornethyl cortical hormones and more specifically to derivatives of M-pregnene-LZO-diones Which have a hydroxy or acyloxy group at 021, a hydroxy group at 0170:, a keto or hydroxy group at 0-11, halogen at C-6oc and/or at C-9cz, and may further have a methyl group at C-Sa and unsaturation at C-l,2.

The novel compounds of the present invention which are potent cortical hormones exhibiting glycogenic, antiinfiammatory, thymolytic, catabolic, anti-androgenic, anti-estrogenic and anti-gonadotrophic activities as Well as suppress the pituitary, are represented by the following formulas:

In the above formulas, Y represents p-hydroxy or keto; X represents hydrogen, chlorine or fluorine; Z represents a double bond or a saturated linkage between (3-1 and 02; R represents hydrogen, methyl, fluorine or chlorine and R represents hydrogen or the acyl radical of a hydrocarbon carboxylic acid of less than 12 carbon atoms, which may be saturated or unsaturated, of straight, branched, cyclic or cyclic-aliphatic chain, aromatic and may be substituted by functional groups such as hydroxy,

alkoxy containing up to 5 carbon atoms, acyloxy containing up to 12 carbon atoms, nitro, amino or halogen. Typical ester groups are the acetate, propionate, enanthate, benzoate, trimethylacetate, t-butylacetate, phenoxyacetate, cyclopentylpropionate, aminoacetate and fl-chloropropionate.

When in the above formulas, R represents hydrogen, fluorine or chlorine, the compounds also possess antifungal and anti-bacterial properties.

The novel compound of the present invention possessing a trifiuoromethyl group at C-16a may be prepared by a process illustrated by the following equation:

eo=o l... qu

CHIOH mop,

V: Y=hydrox I: Y=h drox VII: Y=k9to y VIII: Y=k t0 y CIIiOR (IJHzOR I. OH

Y ---or,

Dry

XI: hydroxy XII: keto In the above equation X represents chlorine or fluorine; Ac represents acetyl or another acyl group derived from hydrocarbon carboxylic acids of less than 12 carbon atoms of the type previously mentioned; Y and R have the same meaning as previously set forth.

In practicing the process outlined above, the starting ago : Y=hydroxy Y=keto material l6a-trifluoromethyl-A -pregnene-3[3,17a-diol-20- one is prepared as described in our copending application Serial No. 63,265, filed of even date, by treating 3fl-acetoxy-A -pregnadiene--one with a trifiuoromethyl magnesium halide, introducing a hydroxyl group at C-17a by forming the enol acetate Mot-trifiuoromethyl- A -pregnadiene-3fl,20-diol diacetate followed by peracid oxidation to form l6a-trifluoromethyl-5,6;17,20- bis-oxido-pregnan-3,8,20-diol diacetate which upon treatment with methanolic potassium hydroxide is converted into 160: trifiuoromethyl 501,60: oxido pregame-36,1704- diol-20-one. The 5(6) double bond is then regenerated by treating the latter compound with zinc and sodium iodide to thus form 16tat-trifiuoromethyl-A -pregnene-3,8, l7a-diol-20-one (1).

Upon oxidation with 8 N-chromic acid in acetone solution followed by treatment of the resulting A -3-ketone with oxalic acid, the latter compound is converted into 16a-trifluoromethyl-M-pregnen-17a-ol-3,20-dione (II).

By monoiodination at C-21 of the 16a-trifiuoromethyl- A -pregnen-17a-ol-3,20-dione as by reaction with an excess of iodine in the presence of a base such as solid calcium oxide in mixture with tetrahydrofuran and methanol (as described by Stork et al. in US. Patent No. 2,874,154), followed by reflux of the thus formed 21-iodo compound with sodium acetate or potassium acetate in mixture with acetone, there is introduced an acetoxy group at C-2l to form 16a-trifiuoromethyl-a -pregnene-17a,21diol-3,20-dione-21-acetate (III). Upon refiux of the latter compound with selenium dioxide in mixture with t-butanol in the presence of catalytic amounts of pyridine or with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, there is formed 16atrifluoromethyl-A -pregnadiene-17a,2l-diol-3,2O dione-. ZI-acetate. The ester group is saponified as by treatment with methanolic potassium hydroxide under an atmosphere of nitrogen for 1 hour at 0 C. By subjecting the thus formed 16a-trifiuoromethy1-A -pregnadiene17u,21- diol-3,20-dione (IV) to microbiological oxidation as by incubation with adrenal glands or with the microorganism Curvularia Iunata ATCC 13935, there is formed 160ttrifiuoromethyl-prednisolone (V; R=hydrogen).

Alternatively 1 6wtrifiuoromethyl-M-pregnene-17a,2 1' diol-2,20-dionc-2l-acetate (III) is saponified with methanolic potassium hydroxide and the thus formed 16m-trifluoromethyl-M-pregnene-17a,21-diol-3,20-dione is similarly subjected to incubation with adrenal glands or with Curvularia lunata ATCC 13935, to finally produce 160:- trifiuoromethyl-hydrocortisone (VI; R=hydrogen) which can be further dehydrogenated at C-1, 2 by treatment with selenium dioxide as described above to afford 16a-trifiuoromethyl-prednisolone (V; R=hydrogen).

Conventional esterification of l6a-trifiuoromethyl-hydrocortisone and of l6a-trifiuoromethyl-prednisolone with hydrocarbon carboxylic acid auhydrides or chlorides of less than 12 carbon atoms followed by oxidation of the thus formed C-21 esters affords the corresponding C-21- esters of 16a-trifiuoromethyl-cortisone (VIII; R=acyl) and 16a-trifluoromethyl-prednisone (VII; R=acy1), which, upon hydrolysis are converted into the free alcohols, 16a-trifluoromethyl-cortisone (VIII; R=hydrogen), and l6a-trifiuoromethyl-prednisone (VII; R=hydrogen).

For introduction of a halogen atom at C-9OC,16tX-tfifiuoromethyl-hydrocortisone acetate is first dehydrated at C-9,1l by reaction with mesyl chloride in dimethylformamide-pyridine solution to produce ld-tl'iflllOl'OlTlfilhYl- M pregnadiene 17,8,21 diol-3,20-dione-2l-acetate. The latter compound is then subjected to the method described by Fried et al., I. Am. Chem. Soc., 79, 1130 (1957). This method entails treatment of the aforementioned compounds with a reagent capable of generating hypobromous acid such as a N-bromoimide or N-bromoamide or the hypobromite of an alkali or alkali-earth me t al, preferably N-bromoacetamide and aqueous perchloric acid in dioxane to produce the bromohydrin. The

latter is refluxed with potassium acetate in dioxane-methanol to form the 9 8,11;8-oxido compound. By reaction with hydrogen fluoride or hydrogen chloride in an inert solvent such as chloroform or a mixture of tetrahydrofurane and methylene chloride under anhydrous conditions and low temperature, there is obtained the corresponding fluorohydrin or chlorohydrin namely, Mix-trifiuoromethyl- 9u-fluoro-hydrocortisone acetate (IX; R=acetyl; X'=fiuorine), and 16a-trifiuoromethyl-9a-chloro-hydrocortisonc acetate, (IX; R=acetyl; X'=chlorine), which upon oxidation with chromic acid is converted into the corresponding l6a-trifiuoromethyl-9a-fluoro-cortisone (X; R=acetyl; X fiuorine) and 16a-trifluoromethyl-9a-chloro-cortisone acetates (X; R=acetyl; X'=chlorine). Upon treatment of the aforementioned hydrocortisone and cortisone compounds with selenium dioxide in t-butanol and in the presence of catalytic amounts of pyridine or with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in dioxane, dehydrogenation at C-1,2 occurs and there is formed the acetates of 16a trifiuoromethyl c fluoro-prednisolone (XI; R=acetyl; X'=fluoro), 16a-trifluoromethyl-9a-chloroprednisolone (XI; R=acetyl; X'=chloro), 16a-trifluoromethyl-9a-fiuoro-prednisone (XII; R=acetyl; X'=fluoro), and a trifiuoromethyl 90c chloro-prednisone (XII; R acetyl; X'=chloro).

The esters are converted into the corresponding free alcohols by treatment with dilute methanolic potassium hydroxide. By conventional esterification with hydrocarbon carboxylic acids anhydrides of the type mentioned previously, other C-21-esters are prepared.

By substituting in the process outlined above the 160:- trifiuoromethyl-d -pregnene-35,l7rx-diol-20-one by 160:- monofluoromethyl-M-pregnene-3,8,17a-diol 20 one prepared in the same manner from 3B-acetoxy-A -pregnadiene-ZG-one except that the trifiuoromethyl magnesium halide is substituted by monofiuoromethyl magnesium halide as is more fully described in our copending application Serial No. 63,265, filed of even date, there is produced all of the above compounds having a monofluoromethyl group at 016m in place of the trifiuoromethyl group. Thus there is produced the novel cortical hormone compounds of the present invention:

l6a-monofluoromethyl-hydrocortisone, 16a-monofiuoromethyl-cortisone, 16a-rnonofiuoromethyl-prednis0lone, 16a-monofiuoromethyl-prednisone, 9e-chloro-16a-monofluoromethyl-hydrocortisone, 9 a-fiuoro-16a-monofluoromethyl-hydrocortisone, 90t-Ch1OIO-16tX-mOIlOflllOl'OHIEIhYl-COI'IISOHC, 9tx-fluorol 6a-monofluoromethyl-cortisone, 9a-chloro-16a-monotluoromethyl-prednisolone, 9a-fluorol 6wmonofluoromethyl-prednisolone, 9u-chloro- 1 6a-monofluoromethyhprednisone and 9cc-fiL10r0-1 6a-monofluoromethyl-prednisone.

By applying the process outlined above to 6-methyl- 16ot-trifluoromethyl-A -pregnene 35,170: diol-ZO-one and the corresponding 16ix-monofiuoromethyl derivatives prepared as disclosed in our copending application Serial No. 63,265, filed of even date, fro-m 6-methyl-A -pregnadien-3fl-o1-20-one acetate (described by Petrow et al., I. Chem. Soc., 4,096, 1957) instead of the l6a-trifluoromethyl-A -pregnene-3fi,17a-diol-20-onc, there are prepared the corresponding compounds having a methyl group at C-6. Thus there is obtained in a consecutive manner, the following compounds,

a mixture of C-20 epimers of a magnesium halide enolate of 6-methyl-Mot-trifiuoromethyl A pregnen-3 {3-01-20- one;

the diacetate of 6-methyl-16a-trifluoromethyl-A pregnadiene-3fi,20-diol;

the diacetate of 6-methyl-16a-trifiuoromethyl-5,6;17,20-

dioxide-pregnane-3/3,20-diol;

5 6-methyl-16a-trifluoromethyl-S,6-oxido-pregna-ne- 3,8,17a-di01-20-0r1e; 6-methyl-1 6ot-tliflll010l'll6 thyl-A -pregnene-3 ,3, 17u-diol- 20-one; Ga-methyI-l6a-trifluoromethyl-17a-hydr0Xy-A -pregnone-3,20-dione; 6ot-methyl-16a-trifluoromethyl-2l-aoetoxy-A -pregnen- 17a-ol-3,20-dione and 6a-methyl-16a-trifluoromethyl-A -pregnadiene-17a,21-

diol-3,20-dione, 6ot-methyl-l6ot-trifluorome-thyl-hydrocor-tisone, Ga-methyl-I6ot-trifluorornethyl-cortisone, 6ot-methyl 1fia-trifluoromethyl-prednisolone, 6a-methyl-16a-trifiuoromethyl-prednisone, 6ozmethyl-9 x-chloro-16a-trifluoromethyl-hydrocortisone, 6a-methyl-9u-fluoro-16a-trifiuoromethyl-hydrocortisone, 6a-methyl-9a-chloro-16rx-trifluoromethyl-cortisone, 6a-methyl-9a-fiuoro-16a-trifluoromethyl-contisone, 6a-methyl-9a-chloro-16or-trifluoromethyl-pred-nisolone, 6u-methyl-9a-fiuoro-l6ct-trifluoromethyl-prednisolone, 6ot-methyl-9a-chloro-l 6u-trifiuoromethyl-prednisone, 6a-methyl-9 oc-fiu oro-l fia-trifiuoromethyl-prednis one and the corresponding 16oc-monofiuoromethy1 derivatives of the above compounds.

Alternatively the above novel compounds of the present invention having a trifiuoromethyl group at C-16a and a methyl group at C-6oc may be prepared by a process illustrated by the following equation:

O CH: 1 l :0 0 Ina-OH aneOH JM lqmgp, I I 110 HO I XIII (IJH EH3 0:0 010E I IIIOH l ...OF3 (\l jmop OH CH; CHs

XV XIV CH2OR ([lHzOR 5: 0:0

nlaOH Inn-OH (\l (\rjm l out (5113 XVI XIX (IJHIOR CHzOR (1:0 0:0 I. I F: ort I I 0: t 0:

out on;

XVII: Y=hydroxy XX: Y=hydroxy XVIII: Y=keto XXI: Y=keto (IJHZOR ({JHaOR i t ---0H 'avOH Y ---or, Y ---CF I X X I I O: O

6H; CH:

XXII XXIII In the above equation, R and X have the same meaning as set forth previously.

In practicing the process outlined above the keto group of 16ct-trifluoromethyl-A -pregnene-3B,l7a-diol-20-one (I) is protected by formation of the cyclic ketal by conventional reaction with a glycol such as ethylene glycol, followed by oxidation of the 5(6) double bond with a peracid such as monoperphthalic or perbenzoic acid to form 16m trifluoromethyl-5a,6ot-oxido-20-ethylenedioxypregnane-3/3,17a-diol (XIII). Treatment of the 501,60:- oxido compound with methyl magnesium halide, preferably methyl magnesium bromide, followed by ammonium chloride decomposition of the Grignard reagent results in the formation of the 6fl-methyl-5a-hydroxy compound, and by further treatment with an acid such as p-toluenesulfonic acid in acetone at reflux temperature, hydrolysis of the cyclic ketal group is effected to thus form trifluoromethyl-6fi-methyl-pregnane-35,5,17a triol 20- one (XIV). Upon oxidation of the latter compound with chromium trioxide in acetone, the 3B-hydroxy group is converted into the 3-keto group to produce 16a-trifluoromethyl-Ga-methyl-pregnane-Sm,17a-diol-3,20-dione which upon reaction with methanolic potassium hydroxide results in dehydration at G5 with introduction of the double bond at 04(5) and concomitant inversion of the 6 8- methyl group to produce 16u-trifiuorornethyl-6a-methyl- A -pregnen-17a-ol-3,20-dione (XV) (16ot-trifluoromethyloa-methyl-17ot-hydroxy-progesterone). The latter compound is then converted, stepwise, into the C-21-iodo, C-ZI-acetoxy (XVI: R=acetyl) and C-21-hydroxy compound (XVI: R=hydrogen) in the same manner as described for the C-6 unsubstituted compound. By subjecting the thus formed 16oa-trifluoromethyl-6a-methyl- A -pregnene-l7ot,2l-diol-3,20-di0ne (XVI: R=hydrogen) to microbiological oxidation as described previously, there is formed 1oa-trifluoromethyl-6a-methylhydrocortisone (XVII: R=hydrogen) which upon conventional esterification is converted into the C-21-ester derivatives (XVII: R acyl). Oxidation of the latter compounds give the 16a-trifiuoromethyl-6a-methyl-cortisone (XVIII: R=hydrogen) and the C-Zl-ester (XVIII: R acyl). A double bond can then be introduced at C-l,2 in the above compounds as by treatment with selenium dioxide or 2,3-diehloro 5,6 dicyano-1,4-benzoquinone as set forth previously to form the corresponding prednisolone and prednisone derivatives and the esters thereof with hydrocarbon carboxylic acid esters of the type hereinabove set forth (XX) and (XXI).

For introduction of a halogen atom at C-9a,16oL-ttifluoromethyl 60c methyl-hydrocortisone acetate (XVII: R=acetyl) is first dehydrated at C-9(ll) and then by following the method of Fried et al. as described previously there is formed the 9u-fiuoro and 9zx-Chl01'0 derivatives of 16a-trifluoromethyl-6u-methyl-hydrocortisone and of 150:- trifiuoromethyl-6a-methyl-cortisone acetates (XXII). By dehydrogenation at C-l,2 by the method described for the C-6 unsubstituted compounds there is formed the C-21 acetates of a-methyl-16u-trifiuoromethyl-9a-fluoroprednisolone, 6a methyl-16a-trifluoromethyl-9a-chloroprednisolone, 6a-methyl-l6u-trifluoromethyl 90c fluoroprednisone and a-methyl-l6a-trifluoromethyl-9tit-chloroprednisone (XXIII). Alkaline hydrolysis of all of the above esters give the corresponding C-2l alcohols which can then be esterified with other hydrocarbon carboxylic acid anhydrides or chlorides of less than 12 carbon atoms by conventional methods to give the corresponding C-2l esters. The dehydrogenation at C-1,2 may be elfected prior to the introduction of the hydroxyl group at C-ll by microbiological oxidation thus producing 6a-methyl- 16m-trifluoromethyl-A -pregnadiene-l7a,21-diol-3,20 dione (XIX: R=hydrogen) from 6a-methyl-16a-trifiuoromethyl-A -pregnene-17a,21-diol-3,20-dione (XVI: R=hydrogen). Upon microbiological oxidation in the manner described above, the l-dehydro compound (XIX: R=hy drogen) is converted into 6oz-methyl-l6a-trifluoromethyl prednisolone (XX: R=hydrogen) which upon further oxidation with chromic acid is transformed into 60:- methyl-16wtrifluoromethyl-prednisone (XXI: R=hydrogen). A halogen atom may then be introduced at C-9u in the manner described above to afford 9ac-chloro and 9zz-fil10t0 derivatives of 6a-methyl-l6wtrifluoromethylprednisolone and of Ga-methyl-l6ot-trifiuoromethyl prednisone (XXIII) and the esters thereof.

In a similar manner by following the process outlined above, there are prepared the corresponding fiot-HICII'IYI- 16a monofluoromethyl derivatives by substituting the starting material 16a-trifluoromethyl-A -pregnene-3p3,17adiol-ZO-one by 16ot-monofiuoromethyl-A pregnene 3 5, l7a-diol-20-one.

The novel compounds of the present invention having a trifiuorornethyl group at C-16a and a fluoro group at C-6oz may be prepared by a process illustrated by the following equation:

I l l 0 i F r XXVI xxv (2132011 (llHaoR XXVIII: Y=hydroxy XXIX: Y keto In the above formulas, X, Y, Z and R have the same meaning as previously set forth.

In practicing the process outlined above, N-brornoacetamide is added together with a solution of IGa-tl'iflllOlO- methyl-A -pregnene-3fi,17a-diol-20-one (I) to a large excess of anhydrous hydrogen fluoride mixed with tetrahydrofurane at -70. The reaction mixture is maintained at 70 C. for 4 hours to form IGm-U'ifiUOI'OmGthYl-Sabromo-6/3-fluoro-pregnane-3;3,17ot-diol 20 one (XXIV). Upon oxidation with 8 N chromic acid, the 3fl-hydroxy group is converted to the 3-keto group and by subsequent reaction With sodium acetate and methanol, dehydrobromination at C-5 is effected to form 6B-fiuoro-l6a-trifluorornethyl-A pregnen l7aol 3,20 dione (XXV). Upon reaction of the latter compound with a mineral acid, inversion of the steric configuration at G6 is effected and there is formed 6u-fluor0-16a-trifluoromethyl-M-pregnen- 17oc-Ol-3,20-di0116 (XXVI). A hydroxy group is then introduced at 0-21 by the method of Stork et a1. and Ringold et al., supra, to afford 6a-fluoro-16a-trifiuoromethyl-A pregnene-l7a,2l-diol 3,20 dione (XXVII: Z==saturated linkage; R=hydrogen) and the Zl-acetate (XXVII: Z=saturated linkage; R= acetyl).

thereof 1 By subjecting the thus formed 6ot-fluoro-16a-trifluoromethyl-M-pregnene 1704,21 diol 3,20 dione (XXVII': Z=saturated linkage; R=hydrgen) to microbiological oxidation as set forth above for the C-6 unsubstituted compound, followed by conventional esterification with acetic anhydride, there is formed 16tX-UiflUOI0I'H6thyl-6arfiUOI'0 hydrocortisone (XXVIII: Z=saturated linkage; R=hydrogen) and its 21-acetate (XXVIII: Z=saturated linkage; R=acetyl), respectively, which can be oxidized with chromic acid to form 16a-trifiuoromethyl-6a-fluoro-cortisone (XXIX: Z=saturated linkage; R=hydrogen) and its Zl-acetate (XXIX: Z=saturated linkage; R=acetyl).

In the same manner as set forth previously, the lfiwtllfiuoromethyl-6a-fluoro-hydrocortisone or its 2l-acetate is dehydrogenated at C-1, 2 to form 16u-trifluoromethyl-6afluoro-prednisolone (XXVIII: Z=double bond; R=hydrogen) which, by oxidation is converted into 16ot-trifluoromethyl-Ga-fluoro-prednisone (XXIX: Z=double bond; R=hydrogen) and the corresponding 21-acetates thereof.

By subjecting 16a-trifluoromethyl-6a-fluoro hydrocortisone-Zl-a'cetate to dehydration and then following the method of Fried et al., supra, there is formed the 9a-fluoro and 9a-chloro derivatives of 16rx-trifiuoromethyl-6a-fluoro-hydrocortisone acetate (XXX: Z=saturated linkage; R=acetyl) and of lGu-trifluoromethyl-6oz-fluoro-cortisone acetate (XXXI: Z=saturated linkage; R=acetyl). By subsequent treatment with selenium dioxide there is formed the C-2 l-acetates of 16a-trifiuoromethyl-6o,9a-difiuoro-prednisolone, (XXX: Z=double bond, R=acetyl); 16a-triiiuoromethyl 60c fluoro 90c chloro-prednisolone (XXX: Z=double bond, R=acetyl), 16a-trifluoromethyl- 6u,9a difluoro prednisone (XXXI: Z=double bond; R=acetyl), and 16a-trifiuoromethyl-Gm-fluoro-9a-chloroprednisone (XXXI: Z=double bond; R=acetyl). Alkaline hydrolysis of all of the above esters give the corresponding C-21 alcohols which can be acylated by conventional methods with other hydrocarbon carboxylic acid anhydrides or chlorides of less than 12 carbon atoms to obtain the corresponding C-21 esters.

The novel compounds of the present invention having a monofluoromethyl group at C-16oc and a fiuoro group at C-6oz may be prepared in the same manner described above'for the 16u-trifluoromethyl series by startingwith 16oz monofluorornethyl-A -pregnene-BB,l7a-diol-2Tone instead of the corresponding la-trifluoromethyl compound.

Alternatively the fluoro group may be introduced at C-6 by'treating 16u-monofluoromethyl or '16u-trifluoromethyl-A -pregene-3fl,17-diol-20-one with a peracid such as monoperphthalic or perbenzoic acid to oxidize the 5,6 double bond to thus form the 5a,6a-oxido derivative. Upon reaction of the latter compound with fluoroboric acid, in accordance with the method described in copending application Serial No. 26,703, filed on May 4, 1960, the oxido ring is opened and there is formed the 16vx-monoiluoromethylor 16a-trifluoromethyl-fiB-fluoropregnane-3,B,5 x,l7a-triol-20-one. The 3-hydroxy group is converted into the 3-keto group upon oxidation with chromic acid and upon further reaction with concentrated hydrochloric acid, dehydration is elfected at G5 with simultaneous inversion of the steric configuration at O6 to form lu-rnonofluoromethylor l6a-trifluoromethyl-6wfluoro-A -pregnen-17a-ol-3,20-dione. The 021 hydroxy group may then be introduced by subsequent microbiologiacl oxidation and dehydrogenation at C-l,2 as described above, the novel cortical compounds of the present invention having a GOL-fillOI'O and a l6oz-monofluorornethyl or 16a-trifluoromethyl group are produced.

The novel compounds of the present invention having a trifluoromethyl group at C-16oc and a chloro group 10 at C-6a may be prepared by a process illustrated by the following equation:

XXXVIII: Y=hydroxy XXXIX: Y=keto In the above formulas, R, X, Y and Z have the same meaning as previously defined.

In practicing the process outlined above, 16oc-tllfill0l'0- methyl-A -pregnene-3B,l7u-diol-20-one (I) is reacted with a peracid such as monoperphthalic acid or perbenzoic acid to oxidize the 5(6) double bond to form the corresponding 5a,6a-oxido compound (XXXII). Upon treatment of the latter compound with concentrated hydrochloric acid in glacial acetic acid, there is formed a trifluoromethyl-6 8-chloro-pregnane-3 8,5a,l7a-triol- 20 -one (XXXIII) which upon oxidation with chromic acid 1s converted into 16u-trifluoromethyl-6B-chloro- 5a,17o-diol-3,20-dione. Treatment of the latter compound in glacial acetic acid with dry hydrochloric acid 1 1 results in the inversion of the steric configuration at C-6 and there is afforded 16u-trifiuoromethyl-Ga-chloro- A -pregnene-17a-ol-3,ZO-dione (XXXIV). By following the methods described previously there is introduced a hydroxy group at C-21, a hydroxy or keto group at 011, a chloro or fluoro group at C-9a to thus form 160: trifluoromethyl 6a-chloro-A -pregnene-17a,2l-diol- 3,20-dione (XXXV), 16lx-trifiuroromethyl-6a-chloro-hydrocortisone (}O(XVI: Z=saturated linkage; R=hydrogen); 16u-trifluoromethyl-6a-chloro-cortisone (XXXVII:

:saturated linkage; R=hydrogen), IGa-trifluoromethyl- 6a-chloro-9a-fluoro-hydrocortisone (XXXVIII: Z=saturated linkage; R=hydrogen), 16a-trifluoromethyl-6achloro-9a-fiuoro-cortisone (XXXIX: Z=saturated linkage; R=hydrogen); 16a-trifluoromethyl-6a,9a lich1orohydrocortisone (XXXVIII: Z=saturated linkage; R: hydrogen), l6a-trifluoromethyl-6u,9u-dichloro-cortisone (XXXIX: Z=saturated linkage; R=hydrogen) and the corresponding l-dehydro derivatives and C-21 esters with hydrocarbon carboxylic acid esters as described heretofore.

By substituting in the process just outlined the 160:- trifluoromethyl-A -pregnene-3B,l7a-diol-20-one by 160:- monofluoromethyl-A -pregnene-3B,l7a-diol-2O-one, there is produced all of the above 6-chloro compounds having a monofluoromethyl group at C-16oc instead of a trifluoromethyl group.

Alternatively the 6a-chloro group may be introduced by treating l6a-trifluoromethyl-M-pregnen-17a-ol-3,20-di0ne (II) or the corresponding l6a-monofluoromethyl derivative with ethyl orthoformate to form the enol ether, 16atrifiuoromethyl or 16a-monofiuoromethyl-3-ethoxy-A pregnadiene-l7a-o1-20-one. Upon reaction of the latter in acetone and sodium acetate with N-chlorosuccinimide and acetic acid, there is obtained 16a-triflu0romethyl or 16a-rnonofluoromethyl-Gfi-chloro-A -pregnen-1701-01-330- dione, which upon further reaction with concentrated hydrochloric acid and acetic acid results in inversion of the steric configuration at O6 to form 16a-trifluoromethyl or 16e-monofiuoromethyl-6a-chloro-A -pregnen-1711-01-3,20- dione which can then be converted to the hydrocortisone and cortisone derivatives in the manner set forth above.

The novel compounds of the present invention possessing a difluorornethyl group at C-16a are prepared by a process illustrated by the following equation:

9-00011 (\QWCHO MQJ $113 ([IH: 0:0 in-0A0 li 1-0111, fiwnr; i i B20 B20 XLIII XLII Cit pm nt, ("l-0A0 1:0

XLVIII: Y=hydroxy =keto XLIX: Y=kcto In the above formulas, Ac, R, Z and X have the same meaning as previously set forth.

To practice the process outlined above, the starting material, the S-benzoate-ZO-acetate of A -pregnene-3fi,20fidiol-lfia-carboxylic acid (XL) is prepared by treating l6a-cyano-A -pregnen-3fl-ol-20-one acetate, described by J. Romo, Tetrahedron 3, 37 (1958), with sodium borohydride to reduce the C-20-keto group to the C-20 hydroxyl group which is then etherified by reaction with dihydropyran in benzene solution and in the presence of ptoluenesulfonic acid. The thus formed ZOfi-tetrahydropyranyloxy-l6a-cyano-A -pregnen-3fl-ol-acetate is hydrolyzed by refluxing with methanolic potassium hydroxide, followed by benzoylation by conventional reaction with benzoyl chloride to afford the 3-benzoyloxy-20fi-tetrahydropyranyloxy-M-pregnene-l6a-carboxylic acid. Hydrolysis of the tetrahydropyranyl ether moiety as by reaction of the latter compound in acetic acid with dilute hydrochloric acid followed by acetylation of the thus formed C-ZOfl alcohol by conventional means affords the starting material, the 3-benzoate-20-acetate of A -pregnene-3fl,20;8- diol-l6a-carboxylic acid (XL). Treatment of the latter compound with oXalyl chloride followed by reduction of the thus formed acid chloride of XL by the reaction with lithium aluminum t-butoxide or by the method of Rosenmund results in the formation of the 3-benzoate-20-aoetate of A -pregnene 35,20 8 diol 16a carboxaldehyde (XLI). The latter compound is then reacted with a large excess of sulfur tetrafluoride in benzene solution for a period of time in the order of 48 hours to effect replacement of the l6a-carboxa1dehyde group by the clifiuoromethyl group and thus form l6wdifluoromethyLM-pregnene-3 S,20fi-diol-3-benzoate-20-acetate (XLII). The ace- XLIV I (3112011 C=O C=O |...0 |...0

Ions; l U -CHF,

XLVI XLVII (JHgOR (3111012. C=O C=O |...0 I... Y qwnr, Y orn, Z X Z L: Y=hydroxy LI Y one.

l3 tate group is saponified as by treatment with methanolic potassium carbonate, followed by oxidation of the thus formed C-ZO alcohol with 8 N chromic acid to produce 16a difiuoromethyl A pregnen-3fi-ol-20-one-benzoate (XLIII), which upon saponification with methanolic potassium carbonate is converted into Mot-difiuoromethyl- A -pregnen-3fi-ol-20-one. The latter compound is subjected to oxidation under Gppenauer conditions to form 160:-

difluoromethylprogesterone (XLIV). I For introduction of a hydroxyl group at 0170:, the intermediate 16ct-difluoromethyl-M-pregnen-BB-ol-ZO-one benzoate (XLIII) is treated in the same manner as the corresponding 16etrifluoromethyl compound. Thus reaction of the intermediate (XLIII) with a mixture of acetic acid and acetyl chloride or with acetic anhydride in the presence of ptoluenesulfonic acid results in the formation of the enol acetate, 16u-difluoromethyl-A -pregnene-3 6,20fl-diol- 3-benzoate-20-acetate (XLV). Upon subsequent reaction with a peracidsuch as peracetic acid, the corresponding Mot-difiuoromethyl 5,6,17,20 dioxido-pregnane 35,20- diol-3-benzoate-20-acetate is formed which upon treatment with a base such as dilute methanolic potassium hydrox'ide under an atmosphere or" nitrogen is converted into 160: difiuoromethyl-5a,6a-oxido-pregnane-3B,17u-diol-20- The latter is then reacted with zinc and sodium iodide in acetic acid to regenerate the 5(6) double bond and the thus formed l6tit-difiuoromethyl-A -pregnene- 3,6,l7a-diol-20-one is subjected to oxidation with 8N chromic acid followed by treatment with dry hydrogen chloride in glacial acetic acid or oxalic acid in methanol solution I to form 16a-difluoromethyl-A -pregnen-1741-01- 3,20 dione (16oz difiuoromethyl-17a-hydroxy-pr0gesterone, XLVI). By monoiodination at 021 of the 1600- difluoromethyl-At-pregnen-17a-ol-3,20-dione as by treatment with an excess of iodine in the presence of calcium oxide as described previously, followed by reaction with potassium acetate in mixture with acetone, there is formed 16a difluoromethyl-n' -pregnene-l7a,21-diol-3,20 dioneill-acetate (XLVII; R=acetyl) which upon saponification with methanolic potassium hydroxide is converted into the free diol (XLVII: R=hydrogen).

In the same manner as set forth previously for the 160ctrifluoromethyl compounds, the 16a-difiuoromethyl-A pregnene-l7ot,2l-diol-El,20-dione is subjected to microbiological oxidation to form l6a-difiuoromethyl-hydrocortisone (XLVIII: Z=saturated linkage, R=hydrogen) which upon conventional esterification is converted into C-2l esters of hydrocarbon carboxylic acids of less than 12 carbon atoms (XLVIII: Z=saturated linkage; R=acyl). Oxidation of the latter compound with 8N chromic acid affords the corresponding C-21 esters of 16adifiuoromethyl-cortisone (XLIX: Z saturated linkage; R=acyl) which upon hydrolysis are converted into the free compound, 16a-difiuoromethyl-cortisone (XLIX; Z=saturated linkage; R=hydrogen).

By reacting IGOt-diflUOl'OHlfithYl hydrocortisone acetate (XLVIII: Z=saturated linkage; R=acetyl) with 2,3- difluoro-5,6-dicyano-l,4-benzoquinone dehydrogenation is effected at C-1, 2 and there is formed Mot-difiuoromethylprednisolone (XLVIH: Z=double bond; R=hydrogen) which upon oxidation is converted into 16a-diflll0l'0- methyl-prednisone (XLIX: Z=double bond; R=hydrogen).

For introduction of a halogen atom at C-9a,l6x-difinoromethylhydrocortisone acetate (XLVIII: Z=saturated linkage; R=acetyl) is dehydrated at C-9(11) and by employing the method of Fried et al., supra, there is finally formed the 9a-fiuoro and 9ot-chloro derivatives of l6a-difiuoromethyl-hydrocortisone acetate (L: Z=saturated linkage; R=acetyl) and of l6ot-difiuoromethylcortisone acetate (LI: Z=saturated linkage; R=acetyl). The reaction of the latter compounds with 2,3-dichloro- 5,6-dicyano-l,4-benzoquinone effects dehydrogenation at O1, 2 to produce the 9a-fiuoro and 9a-chloro derivatives of l6a-difiuoromethyl-prednisolone acetate (X: Z=double 2d bond; R=acetyl) and of -l6ot-difiuoromethyl-prednisone acetate (LI: Z=double bond; R=acetyl). -Alkaline hydrolysis of the above esters produces the free compounds which can be reesterified at 021 with other hydrocarbon carboxylic acid anhydrides or chlorides by conventional methods.

For preparation of the novel compounds of the present invention having a difiuoromethyl group at C-16wand a fluoro group at C-6ot,'16oc-difluoromethyl-A -pregnene-3,8; 17u-diol-20-one is subjected to the same reactions as set forth for the corresponding l6a-trifluoromethyl-A -pregnene-Sdlh-diol-ZO-one compound. Thus there is first formed the 5a-bromo-6B-fluoro compound and by the steps described previously there is formed 160L-difill0l0- methyl 6a-tluoro-A -pregnene-l7a-21-diol-3,2O-dione-2lacetate, 16a-difiuoromethyl-6a-fluoro-A pregnene-l7a,2ldiol-3,20-dione, 16a-difluoromethyl-6ot-fiuoro-hydrocortisone and the C-ZI-esters, 16a-difluoromethyl-6a-fluorocortisone and the C-2l-esters thereof, as well as the free compounds and (3-21 esters of 16u-difiuoromethyl-6afluoro-prednisolone, l6ot-difluoromethyl-6a-fluoro-prednisone, 16a difiuoromethyl-6a,9a-difluoro-hydrocortisone, 16a-difluoromethyl-6a;9a-difluoroprednisolone; 16a-difluoromethyl-6u,9ot-difiuoro-cortisone, 16oz difiuoromethyl- 6a,9a difiuoro prednisone, 16oz difiuoromethyl 6afluoro-9a-chloro-hydrocortisone, 160:. difiuoromethyl 6o:- fluoro-9a-chloroprednisolone, 16a difiuoromethyl 60cfluoro-9a-chlorocortisone and 1604 difiuoromethyl 6ozfluoro-9a-chloroprednisone.

The novel compounds of the present invention having a difiuoromethyl group at C-16 and a methyl or chloro group at (3-60: are prepared in the same manner as the corresponding 16ot-trifluoromethyl-compounds except that l6ot-difiuoromethyl-A -pregnene-3p,17a-diol-20-one is employed as the starting material and there is thus formed the 16a-difluoromethyl-6a-methyl or dot-chloro-A -pregnen-l7a-ol-3,20-dione, which is successively converted into 16ot-difluoromethyl-6a-methyl or 6ot-chloro-A -pregnene-17a,21-diol-3,20-dione-2l-acetate, 16OL-dlfill0l'0l'l16thyl-6u-methyl or 6a-chloro-A -pregnene-l7ot,2l-diol-3,2O- dione, 16ot-difiuoromethyl-6oc-methyl or 6a-chloro-hydrocortisone, and the C-21-esters thereof, Mot-difiuoromethyl-6a-methyl or 6a-chloro-cortisone, the C-21-esters thereof, 16a-difluoromethyl-6a-methyl or 6OC-ChlOI'O-Pl'6dfil80- lone, the C-Zl-esters thereof, 16a-difluoromethyl-6tx-methyl or 6tx-chloro-prednisone, the C-21-esters thereof, as well as the 9ot-fluoro and 9ec-chloro derivatives of the preceding 16a difiuoromethyl-6ot-methyl or 6ot-chloro-hydrocortisone, cortisone, prednisolone and prednisone compounds.

The following specific examples serve to illustrate but are not intended to limit the scope of the present invention:

'Example I 5 g. of 16u-trifluorornethyl-A -pregnene-318,l7ct-diol-2O- one described in our copending application Serial No. 63,265, filed of even date, were dissolved in 50 cc. of acetone, cooled to 0 (3., flushed With nitrogen and treated under stirring with 8 N chromic acid solution, added in a thin stream, at 0 C., until the red color of chromium trioxide persisted in the mixture (the 8 N solution of chromic acid was prepared by dissolving 26.7 g. of chromium trioxide in 23 cc. of concentrated sulfuric acid and diluting with water to cc.). After diluting the mixture with water the product was collected by filtration, Washed with water and dried under vacuum.

The crude product was dissolved in 200' cc. of methanol and treated at room temperature with a solution of 0.5 g. of oxalic acid in 5 cc. of water. The mixture was kept standing for 3 hours, then treated with Water and the product Was collected by filtration, washed with water to neutral and dried. There was thus obtained l6a-trifiuoromethyl-l7a-hydroxy-A -pregnene3,20-dione.

To a solution of 3.9 g. of l6a-trifiuoromethyl-17a-hydroxy-A -pregnene-3,20-dione in 30 cc. of tetrahydrofurane and 18 cc. of methanol was added under vigorous stirring 6 g. of calcium oxide and then 6 g. of iodine; the stirring was continued at room temperature until the color of the solution became pale yellow and then the mixture was poured into ice water containing 15 cc. of acetic acid and 2.1 g. of sodium thiosulfate, the mixture was stirred for 15 minutes, most of the liquid was separated by decantation and the precipitate was collected, washed with water and dried under vacuum. There was thus obtained 16a-trifluoromethyl-17a-hydroxy-2l-iodo- A -pregnene-3,20-dione.

The above substance was mixed with 105 g. of anhydrous acetone and 12 g. of recently fused potassium acetate and refluxed for 8 hours, concentrated to a small volume under reduced pressure and diluted with water; the product was extracted with ether, washed with water, dried over anhydrous sodium sulfate and the ether was evaporated. Recrystallization of the residue from acetone-hexane yielded the 21-acetate of 16u-trifluoromethyl- A -pregnene-l7a,21-diol-3,20-dione.

A mixture of 1.16 g. of the above compound, 120 cc. of t-butanol, 2 cc. of pyridine and 600 mg. of selenium dioxide was refluxed under an atmosphere of nitrogen for 72 hours; after cooling the mixture was diluted with ethyl acetate and filtered through celite; the filtrate was evaporated to dryness under reduced pressure, the residue was triturated with water and the solid collected, washed with water and dried. Recrystallization from methylene chloride-hexane atforded 560 mg. of the 21-acetate of 16atrifluoromethyl-N' -pregnadiene-17a,21-diol-3,20-dione.

Example 11 A solution of the above compound in 20 cc. of methanol was mixed with 2.8 cc. of a 1% solution of potassium hydroxide in water and stirred at C. under an atmosphere of nitrogen for 1 hour; it was then neutralized with acetic acid and the methanol was distilled under reduced pressure. The residue was triturated with water and the solid was collected, washed with water, dried and recrystallized from ethyl acetate-methanol, thus giving approximately 475 mg. of 16a-trifluoromethyl-A -pregnadime-171,21diol-3,2O-dione.

A strain of Curvularia lunata ATCC 13935, was grown in a Sabourini-glucose-agar medium (Difco). The growth obtained after incubating for a week at 25 C. was suspended in cc. of sterile tap water. This suspension was divided in 5 portions of 1 cc. each which were employed for inoculating 5 Erlenmeyer flasks of 250 cc. capacity containing each 50 cc. of a culture medium of the following composition:

Glucose 20 (MHQ HPO 5 NEINO3 3 K HPO 1 MgSO .7H 0 0.2 KCl 0.5 ZnSO Traces FeSO .7H O Traces Distilled water to complete 1 lt.

The cultures were incubated under rotatory stirring for 72 hours at 25 C. The growth was homogenized for 1 minute in a Waring Blendor; 2 cc. portions of the suspension thus obtained were employed for inoculating approximately 100 Erlenmeyer flasks containing the same medium described above. The mixtures were incubated for 24 hours under rotatory stirring at 25 C. and 280 r.p.m.; to each flask there was added 0.5 cc. of a solution of 0.5 g. of 16a-trifluoromethyl-A -pregnadiene-170:,21- diol-3,20-dione in 50 cc. of 95% ethanol and the incubation was continued under the same conditions for 48 hours. The contents of the flasks were combined and extracted with four portions of methylene chloride. The

16 combined extract was dried over anhydrous sodium sulfate and concentrated at low temperature to a volume of 25 cc. This solution was absorbed on 4 g. of silica gel and eluted with methylene chloride acetone (9:1) to produce 200 mg. of pure 16a-trifluoromethyl-prednisolone. The latter was treated with 2 cc. of pyridine and a few drops of acetic anhydride and kept overnight; after diluting with water the solid was collected by filtration and recrystallized from methylene chloride-methanol, thus giving the 21-acetate of 16a-trifluoromethylprednisolone.

Example III A solution of 4 g. of the acetate of 16a-trifluoromethyl- A -pregnene-17a,21-diol-3,20-dione, obtained in accordance with the method of Example 1, in 150 cc. of methanol and 7 cc. of a 4% aqueous solution of potassium hydroxide was stirred for 1 hour under an atmosphere of nitrogen at 0 C.; the mixture was neutralized with acetic acid and the methanol was distilled under reduced pressure. The residue was triturated with water and the solid was collected, washed with water, dried and recrystallized from ethyl acetate-methanol, thus producing 3.05 g. of 16a-trifiuoromethyl-A -pregnene-17a,21-diol- 3,20-dione.

There were prepared the following solutions A, B and C using distilled water as solvent; for preparing solution A there were mixed 425 cc. of 1.74% dipotassium hydrogen phosphate (K HPO and 75 cc. of a 1.38% solution of sodium dihydrogen phosphate (NaH PO solution B was obtained by dissolving 45 g. of sodium chloride, 2.3 g. of potassium chloride and 1.91 g. of magnesium sulfate in water and diluting to a volume of 5 lt.; solution C was obtained by dissolving 20.9 g. of fumaric acid and 14.4 g. of sodium hydroxide in 1.2 lt. of water. There were then mixed 475 cc. of solution A, 4.32 It. of solution B and all of the solution C.

The adrenal glands of recently slaughtered bovine were defatted and ground in a meat grinder to obtain an homogeneous mass; to 3 kg. of this mass was added the mixture of solutions A, B and C and after stirring vigorously there was added 3 g. of 16u-trifluoromethyl- A -pregnene-17a,21-diol-3,20-dione dissolved in 16 cc. of propylene glycol. The mixture was stirred at 28-37 C. for 3 hours and then treated with lt. of acetone and stirred for 1 hour further at room temperature.

The solid was filtered, washed with two portions of 10 1t. each of acetone which were combined and concentrated under reduced pressure to a volume of approximately 5 lt., taking care that the temperature did not rise over 30 C. The solution was then washed with 3 portions of 4 lt. each of hexane, which was discarded; it was then extracted with 2 portions of 3 lt. of methylene chloride and the extract was washed with water, dried over anhydrous sodium sulfate, filtered and concentrated to a volume of 300 cc. under reduced pressure and maintaining the temperature below room temperature. The concentrated solution was allowed to pass through a column of a mixture of g. of silica gel and 90 g. of celite. The column was washed with 3 lt. of methylene chloride and then with l lt. of methylene chlorideacetone (90: 10). The product was eluted with mixtures of methylene chloride and acetone (80:20 and 70:30), the solvent was evaporated and the residue crystallized from ethyl acetate. There was thus obtained 16cctrifluoromethyl-hydrocortisone.

A mixture of 1 g. of the above compound, 10 cc. of pyridine and 2 cc. of anhydride was kept for 3 hours at room temperature and then diluted with Water; the solid was collected by filtration and crystallized from methylene chloride-methanol, thus giving 1.05 g. of the 21-acetate of 1oa-trifiuoromethyl-hydrocortisone.

A mixture of 1 g. of the above compound, 50 cc. of t-butanol, 0.4 g. of recently sublimed selenium dioxide and 0.2 cc. of pyridine was refluxed under an atmosphere of nitrogen for 4-8 hours, cooled, filtered through celite and the filtrate was evaporated under reduced pressure. The residue was refluxed with acetone and recolorizing charcoal for 1 hour, filtered through celite and the solvent was evaporated. By chromatography of the residue on neutral alumina there was obtained the 2l-acetate of 16u-trifluoromethyl-prednisolone, identical with the final product of Example II.

Example IV A mixture of 3 g. of the 21-acetate of 16a-trifluoromethyl-hydrocortisone, obtained in accordance with Example III, 60 cc. of recently distilled dimethylformamide, 3.6 cc. of pyridine and 2.4 cc. of methanesulfonyl chloride was heated for 2 hours at 90 C. The cooled mixture was poured into aqueous saturated sodium bicarbonate solution and the produce was extracted with methylene chloride; the extract was washed with water, dried over anhydrous sodium sulfate and the solvent was evaporated. The residue was chromatographed on 90 g. of silica gel, eluting the product with methylene chloride-acetone (9:1); recrystallization of the product from methylene chloride-methanol yielded 1.6 g. of the 2l-acetate of 1Ga-trifluoromethyl-A pregnadiene-l7u,2l-diol-3,20-dione.

A mixture of 1.38 g. of the above compound and 15 cc. of dioxane was treated with 1.9 cc. of a 0.5 N aqueous solution of perchloric acid and 600 mg. of N-bromoacetamide, adding the latter in the dark, in 3 portions, over a period of half an hour and under continuous stirring. The mixture was stirred in the dark for 1% hours further, the excess or reagent was destroyed by the addition of aqueous sodium bisulfite solution, ice water was added and the product extracted with methylene chloride; the extract was Washed with water, dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure, thus affording the crude 2l-acetate of l6ot-trifluoromethyl-9'x-bromo-hydrocortisone under the form of a yellow oil.

The above crude bromohydrin was refluxed for 6 hours with 2.5 g. of potassium acetate in 60 cc. of acetone. The acetone was distilled, water was added to the residue and the product was extracted with methylene-chloride. The extract was washed with water, dried over anhydrous sodium sulfate and the solvent was evaporated. Recrystallization of the residue from methanol yielded 900 mg. of the 2l-acetate of 16u-trifluoromethy1-9p, llB-oxido- A -pregnene-l7a, 2l-diol-3, 20-dione.

To a solution of 1.6 g. of anhydrous hydrogen fluoride in 2.35 g. of tetrahydrofurane and 10 cc. of methylene chloride, cooled to -60 C., was added a solution of 650 mg. of the above epoxide in 20 cc. methylene chloride. The mixture was kept at 10 C. for 72 hours, poured into aqueous saturated sodium bicarbonate solution and the organic layer was separated, Washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was reacetylated by heating for 1 hour on the steam bath with 3 cc. of acetic anhydride and 6 cc. of pyridine. The liquid was evaporated under reduced pressure and the residue was chromatographed on 30 g. of silica gel. Upon elution with methylene chloride-acetone (9:1), followed by crystallization of the residue from methylene chloride-methanol, there was obtained 290 mg. of the 21- acetate of 16a-trifluoromethyl-9a-iiuoro-hydrocortisone.

By dehydrogenation with selenium dioxide, in accordance with the method described in the last paragraph of the preceding example, there was obtained the 2l-acetate of 1u-triiluoromethyl-9a-fiuoroprednisolone.

100 mg. of the 2l-acetate of l6at-trifluoromethyl-9otfluoroprednisolone was treated with 30 mg. of chromium trioxide in cc. of 80% acetic acid, with stirring and at room temperature for 1 hour. After diluting with water the precipitate was collected, washed and crystallized is from acetone-hexane, thus giving the 2l-acetate of 16atrifluoromethyl-9a-fluoio-prednisone.

Example V By oxidation of the 21-acetate of 16a-trifluoromethyl- 9a-fluoro-hydrocortisone (cf. Example IV) with chromic acid, in accordance with the method described in the preceding example, there was obtained the Zl-acetate of l6m-trifluorome'thyl-9a-fluoro-cortisone.

Similarly, the 2l-acetate of 16a-trifluoromethyl-prednisolone (Example II was converted into the ZI-acetate of l6ot-trifluoromethyl-prednisone, and the Zl-acetate of 160:- trifluorornethyl-hydrocortisone (Example III) was converted into the 21-acetate of 16ot-trifluoromethyl-cortisone.

Example Vl To a polyethylene bottle containing 119 g. of anhydrous tetrahydrofurane was added 70 g. of anhydrous hydrogen fluoride. The mixture was cooled to -70 C. in a Dry Ice-acetone bath and, under vigorous stirring there was added a mixture, previously cooled to 7() C., at 10 g. of 160: trifluoromethyl A -pregnene-3 8, l7a-diol-20-one and 5.0 g. of N-bromoacetamide in 350 ml. of anhydrous methylene chloride distilled over calcium chloride. The mixture was stirred at -70 C. for 4 hours, poured into aqueous saturated sodium carbonate solution and the precipitate was filtered. The organic layer was separated, the aqueous phase was extracted with several portions of methylene chloride and the extracts were combined, washed with water to neutrality, dried over anhydrous sodium sulfate and evaporated to dryness under vacuum. The original precipitate and the residue of the evaporation were combined and crystallized from acetone, thus affording 9.3 g. of l6ot-trifluoromethyl-5a-bromo-fifi-fluoropregnane-3 S, 17a-di0l-20-one.

A solution of 2 g. of the above compound in cc. of acetone was cooled to 0 C. and treated under an atmosphere of nitrogen under stirring with a solution of 8 N chromic acid until the color of the reagent persisted in the mixture. The mixture was then stirred for 10 minutes more at room temperature, diluted with water and the precipitate was collected, washed with water and dried under vacuum, thus aflording 5ot-bromo-6B-fiuoro- 16ot-trifluoromethyl-pregnane-17a-ol-3,20-dione.

The above product was dissolved in methanol and the reaction mixture was treated with 4 g. of anhydrous sodium acetate and refluxed for several hours. The mixture was evaporated to dryness under reduced pressure, Water was added to the residue and the precipitate that formed was collected, washed with water, dried and treated with decolorizing charcoal in acetone solution. The charcoal was removed by filtration, the acetone was evaporated and the residue was crystallized from ethyl acetate-hexane. There was thus obtained 6fl-fiu010-16atrifluoromethyl-A' pregnen-17a-ol-3,20-dione.

A slow stream of dry hydrogen chloride was introduced for 4 hours into a solution of 1 g. of the above compound in 100 cc. of glacial acetic acid, maintaining the temperature around 20 C. The mixture was then poured into ice water and the precipitate was collected by filtration washed with water, dried and recrystallized from ethyl acetate-hexane thus yielding 60t-flUOI'O-160ttrifiuoromethyl-M-pregnen-17a-ol-3,20-dione.

A mixture of 1.5 g. of the above compound, 120 cc. of tertiary butanol, 2 cc. of pyridine and 600 mg. of selenium dioxide was refluxed under an atmosphere of nitrogen for 72 hours. After cooling, the mixture was diluted with ethyl acetate and filtered through celite; the filtrate was evaporated to dryness under reduced pressure, the residue was tri'turated with water and the solid collected, Washed with water and dried. Recrystallization from methylene chloride-hexane afforded 6a-fluoro-l6tt-trifiuoromethyl- A -pregnadien-17a-ol-3,20-dione.

19 Example VII By following the method described in Example I except that 16a trifiuoromethyl A pregnen17a-0l-3,20- dione was replaced by 6a-fluoro-16a-trifluoromethy1-A pregnen-17a-ol-3,20-dione, prepared in the preceding example, there were obtained 6a-fiuor0-Mot-trifiuoromethyl- 21 iodo 17a hydroxy-A -pregnene-3,20-dione and 6afiuoro 16a trifiuoromethyl A pregnene-l7a,21-diol- 3,20-dione ZI-acetate.

800 mg. of the latter compound were dissolved in 16 cc. of methanol and the solution was treated at C. with a solution of 270 mg. of sodium carbonate in 1.6 cc. of water, under an atmosphere 'of nitrogen and under stirring. After 2 /2 hours the mixture was neutralized with acetic acid and the solid was collected, washed with water and dried. There was thus obtained 630 mg. of 16a-trifluoromethyl 6a fluoro A pregnene 170:,21 diol 3,20- dione.

There were prepared additional quantities of the 21- acetate of 16a -trifiuoron1ethyl- 6a fluoro-A pregnene- 17a,2l-diOl-3,20di0l't$. 1 g. of this compound was dehydrogenated to the 2l-acetate of l6ot-tliflll0l0l'l16tl'lYl-6ufiuoro-A -pregnadiene-17a,21-diol-3,20-dione by the reaction with selenium dioxide described in Example I. The product was then hydrolyzed to the free 16u-trifluoromethyl 6a fluoro A pregnadiene 1701,21- diol-3,20-dione by following the procedure of hydrolysis described above. The remaining 21-ace-tate of 160t-Il'lfluoromethyl 6a fiuoro A pregnene 17a,21 diol- 3,20-dione was converted into the free l6a-tllflt10l'0- methyl-60minoro-d -pregnene-17a,21-di0l-3,20-dione.

The l6e-trifluoromethyl-6ot-fiuoro-derivatives of A pregnene-17u,2ldiol-3,20-dione and of the l-dehydro derivatives were then subjected to the reactions described in the case of the 160t-U'lfill0l'0l'll6lll1Yl derivatives without the fluorine substituent at C-6oc.

In accordance with the process described in Example II, by the incubation with Czzrvularia lunata ATCC 13935 1611 trifiuoromethyl 6a fluoro A pregnadienl7a,2l-diol-3,20-dione afforded 16a-trifluoromethy1-6afluoro-prednisolone; by incubation with adrenal glands, in accordance with the method described in Example III, 1611 trifiuoromethyl 6m fluoro A pregnene 1711,21- diol3,20-dione was converted into Mot-trifiuoromethyl- 6u-fiuoro-hydrocortisone. In other experiments there was efiected the 11 fi-hydroxylation of l6a-trifluoromethyl-6afiuoro-d -pregnene-17a,21-diol-3,20-dione by the incubation with Curvularia lmzata, and that of its l-dehydro analog by incubation with adrenal glands.

By the reactions of Example II there was then prepared the 21-acetate of 16a-tritluoromethyl-fia-fiuoro-prednisolone, and by the reactions described in Example III there was prepared the 2l-acetate of 16a-trifiuoromethy1-6mfiuoro-hydrocortisone, and again the 21-acetate of 16atrifiuoromethyl-6a-fluoro-prednisolone.

In accordance with the method described in Example IV there were obtained: the ZI-acetates of 16a-trifluoromethyl 6m fiuoro A pregnadiene 1711,21 diol- 3,20-dione, of 16e-trifluoromethyl-6u-fluoro9a-bromohydrocortisone, of 16a-trifluoromethyl-6a-fluoro-9fi,11poxido A pregnene 17 a,21-dio1-3,20-dione, of 16e-trifiuoromethyl 60,9oc ditluoro-hydrocortisone, of 16a-trifiuoromethyl-6a,9a-difiuoro-prednisolone and of IGzx-il'ifiuoromethyl-6a,9m-difiuoro-prednisone.

In accordance with the method described in Example IV there was oxidized the 21-acetate of 16a-trifiuoromethyl-6a,9tx-difluoro-hydrocortisone to the 21-acetate of 16a-trifluoromethyl-6u,9a-difiuoro-cortisone and the 21- acetate of 16a-trifluorornethyl- 6u,9u difiuoro-prednisolone to the ZI-acetate of 16ot-trifluoromethyl-6a,9u-difiuoro-prednisone.

The methods described in Examples I through IV were repeated starting from the acetate of the 6-methyl derivative of A -pregnadien-3fl-ol-2O-one. There were thus obtained:

20 V 6-methyl-16a-trifiuorornethyl-3,8,20-diacetoxy-A pregnadiene, 3 ,20-diacetoxy-6-methyl-16 oc-tlifilJOIOmGthYl-S ,6; 17,20-

bis-oxido-pregnane, 6-methyl-16u-trifluorornethyl-17a-hydroxy-A -pregnene,

3 ,20-dione,

the 2l-acetate of 6a-rnethyl-l6a-trifluoromethyl-A -pregnene-17a,21-diol-3,20-dione, the Zl-acetate of Got-methyl- 16oz trifiuoromethyl A pregnadiene 1701,21 diol- 3,20-dione, 6a methyl 16a trifiuoromethyl A pregnenel 70:,2 l -diol-3,20-dione and 6a-methyl-16a-trifiuoromethyl-A -pregnadiene-l7a,2l-diol-3,20-dione.

Example VIII The methods described in Examples I through IV were repeated starting from 6methyl-l6a-triflu0romethy1-M- pregnene-BB,l7ct-diol-20-one, described in our aforesaid copending application. There were thus obtained 60:- methyl 160a trifiuoromethyl A pregnen 17a ol- 3,20-dione, the ZI-acetate of 6a methyl 16a -triflu0ro n1ethyl-A -pregnene-l7a,2l-diol-3,20-dione, the 2l-acetate of 6c: methyl 16a trifiuoromethyl-A -pregnadiene- 17a,2l-dioi-3,20-dione and the free 6a-methy1-16a-trifluoromethyl-n -pregnene-17a,21-di0l-3,20-dione and 1- dehydro-derivative thereof.

A portion of the 21-acetate of fia-methyl-la-trifiuoromethyl-A -pregnene 1711,21 diol-3,20-dione mentioned above, was subjected to the transformations described in Example III (starting from the 21-acetate of 16oc-tl'lflll0l0- methyLM-pregnene-17a,21-diol-3,20-dione); there were thus obtained the free 6a-methyl-l6u-trifluoromethyl-A pregnene-l7e,21-diol-3,20-dione, then 6ct-1'116thyl-16a-i1'ifluoromethyl-hydrocortisone, its 2l-acetate and, again, the 21-acetate of 6a-methyl-16a-trifluoromethyl-prednisolone.

By reactions described in Example IV, from the 21- acetate of 6a-methyl-16ot-trifiuoromethyl-hydrocortisone there were obtained: the 21-acetates of 6u-methy1-16atrifiuoromethyl A4301) pregnadicne 17a,2l diol- 3,20-dione, of 60a methyl 16oz trifiuoromethyl 9abrorno-hydrocortisone, of 60a methyl 16oz trifiuoromethyl 93,115 oxido A pregnene 17oc,21 diol- 3,20-dione, of 6a methyl 16oz trifiuoromethyl 9afluoro-prednisolone and of 6a-methy1-16a-trifluoromethyl- 9oc-flllOlO-PI6C1DiSOI1B.

By reactions described in Example V there was oxidized the 21-acetate of Grx-methyl-l6a-trifiuorornethylhydrocortisone to the 21-acetate of 6a-methyl-l6e-trifluoromethyl-cortisone; the 21-acetate of 6a-methyl-16atrifiuoromethyl-9m-fiuoro-hydrocortisone was oxidized to the ZI-acetate of 6a methyl 16oz trifiuoromethyl 9efluoro-cortisone, and the 21-acetate of 6a-methyl-l6a-trifiuoromethyl-prednisolone to the 21-acetate of 6u-methyl- 16e-trifiuoromethyl-prednisone.

Example IX By the method of alkaline hydrolysis described in Example II, or by an alkaline hydrolysis as described in Example VII, the ZI-acetate of the l6a-t1ifiuoromethyl, 16a trifiuoromethyl 6a-fiuoro, 6a-methyl-l6wtrifiuoromethyl, 16cc trifiuoromethyl 9a fiuoro, lfia-trifiuoromethyl-6,9a-ditiuoro and 6a-methyl-1Got-trifiuoromethyl- 9a-fluoro derivatives of cortisone and prednisone were converted into the corresponding free compounds. There were thus obtained all of the lea-trifiuoromethyl hormones under the form of the free alcohols.

Example X A mixture or" 1 g. of 16a-trifiucromethylhydrocortisome, 2 cc. of propionic anhydride and 5 cc. of pyridine was kept at room temperature for 12 hours. It was then poured into cc. of water, heated for 30 minutes on the steam bath, cooled and the precipitate was collected by filtration. The precipitate was washed with water to Example XI By using cyclopentylpropionic anhydride instead of propionic anhydride in the method of esterification described in Example X, there were obtained the 21-cyclopentylpropionates of the compounds set forth in such example.

Example XII By using benzoyl chloride instead of propionic anhydride in the method of esterification described in Example X, there were obtained the 21-benzoates of the compounds set forth in such example.

Example XIII A mixture of 10 g. of 16a-trifluorornethyl-A -pregnene- 35,17a-diol-20-one (cf. Example I), 80 cc. of ethylene glycol, 2 liters of dry benzene and 1.5 g. of p-toluenesulfonic acid monohydrate was refluxed for 18 hours, using a Dean-Stark water separator. The cooled mixture was treated with 5% aqueous sodium bicarbonate, the organic phase was separated, Washed with water, dried over anhydrous sodium sulfate and the solvent was evaporated. Crystallization of the residue from acetone afforded 16atrifluoromethyl-20-ethylenedioxy-A -pregnen-3/3,17e-diol.

A solution of 8 g. of the above compound in 1600 cc. of methylene chloride was cooled to C. and mixed with an ether solution of 6.0 g. of monoperphthalic acid. The mixture was kept at 0 C. for 16 hours, then diluted with water; the organic layer was separated, washed with aqueous sodium bicarbonate solution and then with water to neutrality, dried over anhydrous sodium sulfate and the solvent was evaporated. The residue was purified by crystallization from acetone-hexane. There was thus obtained 16ot-trifiuoromethyl-5a,6a-oxido-2Q-ethylenedioxypregnane-3fl,17u-diol.

A mixture of 5 g. of the above compound and 5 molar equivalents of methylmagnesium bromide in 500 cc. of dry benzene was refluxed for 3 hours, then poured under vigorous stirring into a mixture of 1 liter of 20% aqueous ammonium chloride solution and 1 kg. of ice. The benzene layer was separated, washed with water, dried over anhydrous sodium sulfate and the benzene was evaporated, finally under reduced pressure. The residue was treated with 100 mg. of p-toluenesulfonic acid monohydrate and 300 cc. of acetone and kept at room temperature for 16 hours, diluted with water and the solid collected, thus giving the crude 6fi-methyl-l6oc-trhluoromethylpregnane-3fl,5a,l7u-triol-20-one. The latter was oxidized with 8 N chromic acid, in accordance with the method described in Example I, to produce 6B-methyl-16a-trifiuoromethyl pregnane 5%,170: diol-3,20-dione, which, without further purification, was treated with 250 cc. of 1% methanolic potassium hydroxide under an atmosphere of nitrogen and at room temperature for 8 hours. After acidifying with acetic acid the mixture was concentrated to a small volume under reduced pressure and the product was precipitated by the addition of water. The solid was collected, washed with Water and crystallized from acetone-hexane. There was thus obtained 6a-methy1-16atrifiuoromethyl-M-pregnen-17a-ol-3,20 dione, identical, with the intermediate of Example VIII.

22 Example XIV By substituting in Example I the 16a-trifluoromethyl- A pregnene 35,170; diol-Ztl-one by 16a-monofluoromethyl-A -pregnene-3B,17a-diol-20-one, described in our aforementioned copending application, and applying the methods described in Examples I through V, there were obtained 16a-monofluoromethyl-M-pregnen-17a-ol-3,20-dione,

1 6a-monofluoromethyl-17a-hydroxy-21-iodo-A -pregnene- 3 ,ZG-dione,

16a-monofluoromethyl-A -pregnene-17u,21-diol-3 ,20-

dione-21-acetate,

16a-monofluoromethyl-A -pregnadiene-17a,21-diol-3,20-

dione-Z 1 -acetate,

1 a-monofiuoromethyl-A -pregnadiene17a,2l-diol-3,20-

dione,

1 6a-monofluoromethyl-A -pregnene-17rx,21-diol-3 ,20-

dione,

16 a-m onofluorom ethyl-prednisolone,

16a-monofiuoromethyl-prednisolone-Z l-acetate,

1 6 Ot-III onofluoromethyl-hydrocortisone and its 021 acetate,

1 6a-monoiluoromethyl-9a-iluoro-hydrocortisone-2 1- acetate,

l6a-monofiuoromethyl-9a-fluoro-prednisolone-2 l-acetate,

16a-monofluoromethyl-9a-fiu oro-prednisone-Z l-acetate,

l 6e-monofiuoromethyl-9 a-Iluoro-cOrtiSone-Z l-acetate,

1 6a-monofiuoromethyl-prednisone-2 1 acetate and 1 fizz-IIIOIIOfiHOIOmCthYl-COItiS one-2 l-acetate.

Example XV By substituting in Example V! the la-trifluoromethyl- A pregnene 3,8,17a-diol-20-one by lfiu-monofiuoromethyl-A -pregnene-3B,17a-diol-2O-one there was obtained the intermediates 6:! -fluoro-16a-rnonofluoromethyl-A pregnen-l7c -ol-3,20-dione and the 1-dehydro derivative thereof and by then following the method of Example VII there were obtained all of the corresponding compounds having a monofiuoromethyl group at C-16a in place of the trifiuoromethyl group at C-16oc.

Example XVI By applying the method described in Example VIII to 6 methyl 16ot-monofluoromethyl-M-pregnene-3B,17erdiol-20one instead of 6-methyl-16u-trifiuoromethyl-A pregnen-B/S,17x-diol-20-one, there were obtained 60:- methyl-16a-monofluoromethyl-A -pregnene 17a ol 3, ZO-dione, the 21-acetate of and the free compound 60:- methyl 16a monoiluoromethyLM-pregnene-17o,2l-diol- 3,20-dione, the 21-acetate of and the free compound 60:- methyl 16a monofluoromethyl A pregnadiene-Ua, 21diol-3,20-dione, 6u-methyl-16a-monofluoromethyl-hydrocortisone and its ZI-acetate, the 21-acetate of 61xmethyl-16a-monofiuoromethyl-prednisolone, 6a-methyla monofluoromethyl 9a fluoro prednisolone 21- acetate, Gut-methyl-16a-monofiuoromethyl-9a-fiuoro-prednisone-Zl-acetate, and the 21-acetates of 6rx-methyl-16amonofluoromethyl-cortisone, of 6a-methyl-16a-monofluoromethyl-9a-fiuoro-cortisone, and 6a-methyl-l6a-monofiuoromethyl-prednisone.

Example XVII By applying the method of alkaline hydrolysis described in Example I or by alkaline hydrolysis as described in Example VII, the ZI-acetates of the 16x-monofluoromethyl, 6u-fiuoro-16a-monofiuoromethyl, 6a-methyl-l6etmonofluoromethyl, 9u-fiuoro-1oa-monofiuoromethyl, 6a, 9a-difluoro-16ot-monoiluoromethy1, and Soc-[IlellhYl-9oa-fllloro-16a-monofluoromethyl derivatives of cortisone and prednisone were converted into the corresponding free compounds.

Example XVIII By applying the methods described in Examples X, XI and XII to the corresponding l6u-monofiuoromethyl com- 23 pounds there were obtained the C-Zl-propionates, C-21- cyclopentylpropionates and C-Zl-benzoates of l6a-monofiuoromethyl-hydrocortisone, l6a-monotluoromethyl-cortisone, l6a-monofluorornethyl-prednisone, 16a-monofluoromethyl-prednisolone as well as the 6a-methyl-l6a-monofiuoromethyl, 6a-fluoro-loa-monofluoromethyl, 9u-fiuoro- 16a monofluoromethyl, 60:,90: difluoro-l6a-monofluoromethyl, and 6a-methyl-9a-fiuoro-l6a-monofluoromethyl derivatives of hydrocortisone, prednisolone, cortisone and prednisone.

Example XIX A mixture of 1 g. of the 3-benzoate-20-acetate of A pregnene-3,B,20/8-diol-l6a-carboxylic acid, described in our aforementioned copending application and 5 cc. of oxalyl chloride was refluxed under anhydrous conditions during 2 hours. The solution was evaporated in vacuum, 2 portions of dry benzene were added and reevaporated to eliminate traces of oxalyl chloride. The above crude acid chloride was dissolved in 20 cc. of anhydrous tetrahydrofurane, cooled to -75 C. in a Dry-Ice-acetone bath and treated with a previously cooled solution of 600 mg. of lithium aluminum t-butoxide in 20 cc. of anhydrous tetrahydrofurane. The reaction mixture was kept at --75 C. for 1 hour and then at room temperature for 30 min- H utes, poured into ice water and extracted several times with ethyl acetate, washed with water to neutral, dried over anhydrous sodium sulfate and evaporated to dryness under vacuum. After chromatography there was obtained the 3-benzoate of A -pregnene-3p,20p-diol-l6a-carboxmdehyde.

A solution of 500 mg. of the above aldehyde in 100 cc. of benzene was treated with 1 g. of sulfur tetrafiuoride and the mixture kept in a sealed steel tube for 48 hours at room temperature, it was then poured carefully into ice water. An excess of sodium bicarbonate was added and the product extracted with methylene chloride. The extract was washed with water to neutral, dried and evaporated to dryness. After chromatography and crystallization of the solid fractions from acetone-hexane there was obtained 16oz ditluoromethyl-A -pregnene-3[3,20,6-diol-3- benzoate-ZO-acetate.

For the next step there were combined several batches of the above compound.

Example XX A solution of 5 g. of loa-difiuoromethyl-M-pregnene- 3,3,20,B-diol-3-benzoate-20-acetate in 200 cc. of methanol was treated with 2.5 g. of potassium carbonate dissolved in 20 cc. of water and the mixture kept at room temperature for 12 hours. The reaction mixture was neutralized with acetic acid and concentrated under vacuum to onethird its volume, poured into water, the formed precipitate filtered washed with water to neutral and dried, thus giving 16u-difluoromethy1-A -pregnene-3[3,20B-diol-3-benzoate.

The above crude product was dissolved in 100 cc. of acetone, cooled to 0 C. and treated dropwise under an atmosphere of nitrogen under stirring with an 8 N chromic acid solution (prepared as in Example I) until the color of the reagent persisted in he mixture, stirred for 10 minutes further at room temperature, diluted with water and the precipitate collected, washed with water and dried under vacuum, thus affording l6a-difluoromethyl-A pregnen-3/i-ol-20-one benzoate.

A solution of 3.3 g. of the above compound in 250 ml. of acetic anhydride containing 1.3 g. of p-toluenesulfonic acid was subjected to a slow distillation over a period of 8 hours, the residue was poured into ice water and the product was extracted with ether. The extract was consecutively washed with 5% aqueous sodium carbonate solution and water, dried over anhydrous sodium sulfate and the ether was evaporated. There was thus obtained 16a-difluoromethyl-A -pregnadiene 35,20 diol-3- benzoate-ZO-acetate.

A solution of the above crude enol acetate in 30 cc. of ether was treated with cc. of a l N solution of monoperphthalic acid and the mixture was kept at room temperature for 3 days; at the end of this time it was consecutively washed with dilute sodium chloride solution, sodium carbonate, sodium iodide, sodium thiosulfate and finally with sodium chloride solution; the ether solution was dried over anhydrous sodium sulfate and evaporated to dryness, thus yielding a mixture of 5a,6oz,17,20- bis oxido 16oz difluoromethyl 3 8 benzoyloxy 20- acetoxy-pregnane and of its 5,3,6fl-isomer. This mixture was dissolved in cc. of methanol, treated with 1.5 g. of potassium hydroxide dissolved in 15 cc. of water and refluxed for 3 hours; the mixture was neutralized with acetic acid, concentrated to one-third its volume, poured into ice water and the precipitate formed was collected and dried.

The above crude product was added to a mixture of 2.8 g. of sodium iodide, 0.95 g. of anhydrous sodium acetate, 2.8 g. of zinc dust, 11 cc. of acetic acid and 0.4 cc. of water; the mixture was stirred at room temperature for 3 hours, the zinc was removed by filtration and the solution was poured into ice water. The precipitate formed was collected, washed with water to neutrality, dried, dissolved in 70 cc. of hot dimethyl-formamide, filtered through celite to remove traces of zinc and then hot water was added to crystallize the product; after cooling in ice the precipitate was collected by filtration and washed with methanol, thus affording 1.6 g. of loa-difluorornethyl- A -pregnene-3fi,17e-diol-20-one.

Example XXI A solution of 1.5 g. of the above compound in 20 cc. of acetone was oxidized with 8 N chromic acid solution in accordance with the method of Example I, the crude product was dissolved in 50 cc. of methanol and treated at room temperature with a solution of 150 mg. of oxalic acid in 1.5 cc. of water. The mixture was kept standing for 3 hours, then treated with water and the product was collected by filtration, washed with water to neutral and dried. There was thus obtained l6a-ditluoromethyl-l7uhydroxy-A -pregnene-3,2O-dione.

By following the method of Example I, the above compound was converted into l6a-difluoromethyl-l7a-hydroxy 2l-iodo-A -pregnene-3,20-dione, l6a-difiuoromethyl-M-pregnene-l7a,21-diol-3,20-dione 2l-acetate and 16:1- difluoromethyl-A -pregnadiene-17u,2l-diol-3,20-dione.

By the methods of alkaline hydrolysis described in Example II or in Example VII, the above 2l-acetates were converted into the corresponding free compounds. After incubation with adrenal glands, in accordance with the method of Example III there were obtained l6a-diiluoroinethyl-hydrocortisone and l6a-difluoromethyl-predniso one.

Example XXII A mixture of 500 mg. of l6a-difluoromethyl-hydrocortisone, 10 cc. of dioxane and 350 mg. of 2,3-difluoro- 5,6-dicyano-1,4-benzoquinone was refluxed for 18 hours. It was then cooled, the 2,3-dichloro-5,6-dicyano-1,4- benzohydroquinone formed during the reaction filtered off and the filtrate evaporated to dryness. The residue was dissolved in acetone and filtered through 10 g. of alumina. Crystallization from acetone-hexane gave 16adifiuoromethyl-prednisolone identical with that obtained in the preceding example.

Example XXIII By following the method of Example VI, 5 g. of 16w difluoromethyl A -preguene-3 5,17a-diol-20-one obtained as described in Example XX was converted into 6ot-fiuorol6a-difluoromethyl-A pregnen-l7ot-ol-20-one.

By following the acetoxylation method described in Example I the above compound was converted into 6afluoro 16a diiluoromethyl 21 iodo-l7a-hydroxy-A 25 pregnene-3,20-dione and Ga-itnoro-l6ot-trifluoromethyl-A pregnene-l7a,2l-diol-3,20-dione 2l-acetate.

3.2 g. of the latter compound were dissolved in 60 cc. of methanol and the solution was treated at C. with a solution of 1 g. of sodium carbonate in 6 cc. of Water, under an atmosphere of nitrogen and under stirring. After 2 /2 hours the mixture was neutralized with acetic acid and the solid collected, Washed with water and dried. There was thus obtained 630 mg. of l6a-difluoromethyl- 6a-fluoro-A -pregnene-17a,2l-diol-3,20-dione.

In accordance with the process described in Example II, by the incubation with Curvularia lunata ATCC 13935, 160; trifluoromethyl 6a-fiuoro-A -pregnene17a,21-diol- 3,20-dione aiforded 16a-difluoromethyl-6a-fluoro-hydrocortisone.

750 mg. of the above compound were converted into the corresponding 2l-acetate in a conventional manner. Further treatment with chromium trioxide in acetic acid solution, according to the method of Example IV gave l6a-difiuoromethyl-Sa-fluoro-cortisone acetate.

Example XXIV By the reactions described in Example IV, from the 21- acetate of 6a-fluoro-16m-difluoromethyl-hydrocortisone there were obtained the 2l-acetates of 6a-fil101'O-l6ot-(lifluoromethyl A -pregnadiene-17u,2l-diol-3,20-dione, of 6a-fluoro 16cc difiuoromethyl-9a-bromo-hydrocortisone, of 6a fluoro-l6u-difluoromethyl-9fl,l lfi-oxido-A pregnene l7a,2l-diol-3,20-dione, of 6a,9a-difluoro-l6adifluoromethyl-hydrocortisone, of 6a,9a-difiuoro-l6a-difiuoromethyl-prednisolone and of 60,9oz-dlfitlOIO-16oc-difluoromethyl-prednisone.

Example XXV To a solution of 500 mg. of 6oc-fiuoro-l6a-difluoromethyl 9,8,1lfi-oxido-A pregnene-17a,2l-diol-3,20-dione 2l-acetate obtained as described in the preceding example in 10 cc. of redistilled chloroform was added 4 cc. of a 0.45 N solution of dry hydrogen chloride in chloroform, under continuous stirring and maintaining the temperature around 0 C. The mixture was then stirred at 0 C. for 1 hour further, diluted with water and the chloroform layer was separated, washed with aqueous sodium bicarbonate solution and then with water, dried over anhydrous sodium sulfate and the chloroform was evaporated under reduced pressure. Crystallization of the residue gave the acetate of 6oc-fiLIO1O-9oc-Cl1l0r0-l6oc-dlfl110r0- methyl-hydroco-rtisone.

By dehydrogenation with 2,3-dichloro-5,6-dicyano-1,4- benzoquinone, in accordance with the method of Example XXII, there was obtained 6u-fiuOrO-9oz-0hl0f0-l6cc-dlfluorornethyl-prednisolone acetate.

Example XXVI A solution of g. of l6a-difluoromethyl-l7a-hydroxy- M-pregnene-lZO-dione obtained as described in Example XXI in 40 cc. of peroxide-free dioxane and 5 cc. of freshly distilled ethyl orthoformate was treated with 150 mg. of p-toluenesulfonic acid and the mixture stirred for 1 hour. 0.8 cc. of pyridine was added and then poured into icesalt water, the precipitate was collected and Washed with Water containing a few drops of pyridine, thus giving 16adifiuoromethyl-3-ethoxy-A -pregnadien-l7a-ol-20-one.

A mixture of the above enol ether, 2 g. of anhydrous sodium acetate and 100 parts of acetone was treated with 20 cc. of water and the solution was cooled to a temperature between 0 and 5 C.; there was then added 1.1 molar equivalents of N-chlorosuccinimide and 2 cc. of glacial acetic acid and the mixture was stirred between 0 and 5 C. for 30 minutes. It was then diluted with ice-salt water, kept standing over night in the refrigerator and the precipitate formed was collected, washed with water, dried under vacuum and recrystallized from acetone, There was thus obtained a 65-chloro-l6u-difiuorornethyl- A -pregnen-17u-ol-3,20-dione.

Into a solution of l g. of the above compound in 50 cc.

of glacial acetic acid was passed a slow stream of dry hydrogen chloride for 4 hours, while maintaining the temperature around 15 C.; the mixture was then poured into ice-water, the precipitate was collected, washed with water, dried and recrystallized from acetone-hexane to give 6oz chloro-16a-difluoromethyl-A -pregnen-1704-01-3, 20-dione.

By following the method of Example I, the above compound was converted into 6a-chloro-l6a-difiuoromethyl-17a-hydroxy-21-iodo-A -pregnene-3,2O dione, 6wchloro 16oz difluoromethyl A -pregnene-l7a,21-diol- 3,20-dione acetate and 6oz-Chl0r0- l6a-difiuoromethyl- A -pregnadiene-17 2l-diol-3,20-dione acetate.

Example XX VII A solution of 500 mg. of the 21-acetate of 6a-chlorol6a-difluoromethyl-A -pregnene-17a,2l-diol-3,20-dione in 20 cc. of methanol was mixed with 2.8 cc. of a 1% solution of potassium hydroxide in water and stirred at 0 C. under an atmosphere of nitrogen for 1 hour; it was then neutralized with acetic acid and the methanol was distilled under reduced pressure. The residue was triturated with water and the solid was collected, washed with water, dried and recrystallized from ethyl acetate-methanol, thus giving approximately 430 mg. of 6a-chloro-l6a-difiuoromethyl-A -pregnene-l7a,21-diol-3,20-dione.

The above compound was incubated with adrenal glands in accordance with the method of Example III, thus affording 6ot-chloro-l6a-difluoromethyl-hydrocortisone.

Acetylation of the above compound in a conventional manner, followed by dehydrogenation with selenium dioxide, in accordance with the method of Example III gave the acetate of 6a-chloro-la-difluorornethyl-prednisolone.

Example XXVIH A mixture of l g. of 16a-rnonofluoromethyl-hydrocortisone acetate, 2 g. of chloranil, 15 cc. of ethyl acetate and 5 cc. of acetic acid was refluxed under an atmosphere of nitrogen for 96 hours. The mixture was cooled, washed with a cold aqueous solution of 10% sodium hydroxide until the washings were colorless. The organic solution was dried over anhydrous sodium sulfate and the ethyl acetate was evaporated. By chromatography of the residue on neutral alumina there was obtained the acetate of l6a-rnonofluoromethyl-n -pregnadien-l1,8,l7a,2l-triol-3,20-dione.

In a similar manner, the 2l-acetates of 6a-fiuoro-16amonofiuoromethyl, 6a-methyl-l6a-monofluoromethyl, cfiuoro 16oz monofiuoromethyl, 6a,9a-fluoro 1606-1110110- fluoromethyl, and 60: methyl 9a fluoro 16oz monofluoromethyl derivatives of cortisone and prednisone were converted into the corresponding 6-dehydro derivatives.

Example XXIX By oxidation of the 2l-acetate of 6a-chloro-l6a-monofiuoromethyl-hydrocortisone (cf. Example XXVI) with chromic acid, in accordance with the method of Ex ample IV, there was obtained the ZI-acetate of 6a-chloro- 16a-difluoromethyl-cortisone.

l g. of the above compound was treated with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone by following the method of Example XXII thus giving Goa-ChlOrO-16adifluoromethyl-prednisone acetate.

400 mg. of the latter compound were dissolved in 8 cc. of methanol and the solution treated with mg. of sodium carbonate in 1 cc. of water, under an atmosphere of nitrogen and under stirring, the mixture kept at room temperature for 1 hour and then neutralized with acetic acid, poured into ice water, the formed precipitate collected, washed with water and dried. There was thus obtained 6a-chloro-16a-difluoromethyl-prednisolone.

Example XXX A solution of 5 g. of 16 a-trifluoromethyl-M-pregnene- 3p,l7a-diol-20-one, obtained as described in our copending patent application Serial No. 63,265, filed of even date, in 500 cc. of methylene chloride was cooled to C. and mixed with 1.5 molar equivalents of monoperphthalic acid in ether solution. The mixture was kept at 0 C. for 20 hours, diluted with water, the organic layer was separated, washed with aqueous sodium bicarbonate solution and then with water to neutral, dried over anhydrous sodium sulfate and evaporated to dryness. Crystallization from acetone-hexane gave 3.75 g. of the pure 16a trifluOrOmethyl-Sa,6u-oxido-pregnan-3,8,17a-dio1-20- one.

A solution of 3 g. of the above compound in 300 cc. of glacial acetic acid was treated with 6 cc. of concentrated hydrochloric acid and the mixture kept at room temperature for 6 hours. After dilution with ice-salt water, and filtration of the formed precipitate there was obtained 16:; trifiuoromethyl-6/3-chloro-pregnane-3fi,5a, 17a-triol-20-one. Upon oxidation with 8 N chromic acid solution by following the method of Example I there was obtained l6u-trifluoromethyl-ofi-chloro-pregnane-5a, l7a-diol-3,20-dione.

A slow stream of dry hydrogen chloride was intro duced for 4 hours into a solution of 1 g. of the above compound in 100 cc. of glacial acetic acid, maintaining the temperature around 20 C.; the mixture was poured into ice water and the precipitate collected by filtration, washed with water, dried and recrystallized from acetoneether thus yielding 6a-chloro-l6tx-trifluoromethyl-A pregnen-17a-o1-3,20-dione.

To a solution of 1 g. of the above compound in 7.5 cc. of tetrahydrofurane and 4.5 cc. of methanol was added under vigorous stirring 1.6 g. of calcium oxide and 1.6 g. of iodine; the stirring was continued at room temperature until the color of the solution became pale yellow and then the mixture was poured into ice water containing 4 cc. of acetic acid and 5 g. of sodium thiosulfate, stirred for minutes, most of the liquid was separated by decantation and the precipitate was collected, washed with water and dried under vacuum. There was thus obtained 6a chloro 1fiu-tritluoromethyl-17a-hydroxy-21- iodo-M-pregnene-3,20-dione.

The above substance was mixed with 50 cc. of anhydrous acetone and 4 g. of recently fused potassium acetate and refluxed for 8 hours, concentrated to a small volume under reduced pressure and diluted with water, the solid was filtered and recrystallized from acetone hexane, yielding the 2l-acetate of 6u-chloro-l6a-trifluoromethyl-A pregnene-17a,21-diol-3,20-dione.

By the methods of alkaline hydrolysis described in Example VII, there was obtained the free compound. After incubation with adrenal glands, in accordance with the method of Example III, there was obtained 6oc-Chl0I0-16cctrifluoromethyl-hydrocortisone.

Example XXXI A solution of 1 g. of 6tz-chloro-l6a-trifiuoromethylhydrocortisone in 5 cc. of pyridine was treated for 4 hours with 4 cc. of acetice anhydride, thus giving the corresponding acetate.

The latter compound was oxidized with chromium trioxide in acetic acid in accordance with the method of Example 1V, thus affording 6ot-chloro-16a-trifluoromethylcortisone acetate. Upon treatment with 2,3-dichloro-5,6- dicyano-l,4-benzoquinone, by following the method of Example XXII, there was obtained 6cc-ChlO10-l6et-t1'ifluoromethyl-prednisone acetate.

Example XXXII By following the methods of Examples XXX and XXXI, but using as starting material 16u-monofiuoromethyl-A -pregnene-3t3,17a-diol-20-one, described in our aforementioned copending application, there were obtained 16a monofluoromethyl 501,60: oxido pregnan- 3fi,17a-diol-20-one, 16amonofiuoromethyl 6,8 chloropregnane-3B,5a,17e-triol 20 one, 6B-chloro-16a-monofluoromethyl-pregnane-5a,l7a-diol-3,20-dione, 6a-chlor0- 16a-monofiuoromethyl A pregnen-17a-ol-3,20-dione, 6a-chloro-l6or-monofluoromethyl A- pregnenel7a,21- diol-3,20-dione 21-acetate, 6a-chloro a monofiuoromethyl-A -pregnene-l7cx,21-diol 3,20 dione, 6a-ch1oro- 16cc monofiuoromethyl-hydrocortisone, 6a ChlOIO-16ezmonofiuoromethyl-hydrocortisone acetate, 6nz-Cl1l0r0-l6umonofluoromethyl-cortisone acetate and 6oL-Chl0tO-l6amonofiuoromethyl-prednisone acetate.

We claim:

1. A compound of the following formula:

wherein R is selected from the group consisting of hydrogen and a hydrocarbon carboxylic acyl group of less than 12 carbon atoms; R is selected from the group consisting of hydrogen, methyl, chlorine and fluorine; Y is selected from the group consisting of hydroxy and keto and X is selected from the group consisting of hydrogen, chlorine and fluorine.

2. 6a-methyl-l6a-trifiuoromethyl-cortisone.

3. 6a,9a-difluoro-16a-trifluoromethyl-hydrocortisone.

4. 16wtrifluoromethyl-hydrocortisone.

5. A compound of the following formula:

CHZOR qmcp l CHzOR Y ---CHF2 CIIaOR RI wherein R is selected from the group consisting of hydrogen and a hydrocarbon carboxylic acyl group of less than 12 carbon atoms; R is selected from the group consisting of hydrogen, methyl, chlorine and fluorine; Y is selected from the group consisting of hydroxy and keto and X is selected from the group consisting of hydrogen, chlorine and fluorine.

9. 16a.-trifluoromethyl-prednisolone-Zl-acetate.

10. 6a-rnethyl-16ot-trifluorornethyl prednisone.

11. 6a-fluoro-16a-trifluoromethyl prednisolone.

12. A compound of the following formula:

CHzOR I. OH IHOHF,

wherein R is selected from the group consisting of hydrogen and a hydrocarbon carboxylic acyl group of less than 12 carbon atoms; R is selected from the group consisting of hydrogen, methyl, chlorine and fluorine; Y is selected from the group consisting of hydroxy and keto and X is selected from the group consisting of hydrogen, chlorine and fluorine.

13. 6a-chIoro-9u-fluoro-16a-difluoromethyl-prednisone.

14. 6u-methy1-9u-fiuoro 16a difluoromethyl-prednisolone.

15. 6a-fluoro-16a-difiuoromethyl-prednisolone.

No references cited. 

1. A COMPOUND OF THE FOLLOWING FORMULA: 